Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Claesson, Hans‐Erik; Se, Dahlén

doi:10.1046/j.1365-2796.1999.00418.x

Cited by 101 publications

(87 citation statements)

References 241 publications

(344 reference statements)

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“…It is also possible that differences in the production of and/or response to LTB 4 may contribute to the strain variation seen in the 5LO-dependent component of inflammatory responses. In humans, it has been suggested that increased production of cysteinyl-LT correlates with susceptibility to aspirin-intolerant asthma (37,38). Recent studies have shown that variations in the synthesis of cysteinyl-LT result from a polymorphism in the LTC 4 synthase gene promoter, which causes constitutive overexpression of this enzyme in aspirin-sensitive patients (37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that variations in the synthesis of cysteinyl-LT result from a polymorphism in the LTC 4 synthase gene promoter, which causes constitutive overexpression of this enzyme in aspirin-sensitive patients (37)(38)(39)(40). Differing expression levels of LTC 4 synthase may account for variability observed in the response to LT inhibitors used in the treatment of asthma (37).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

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Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence of genetic factors on the contribution of LT to acute inflammation, we generated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical application of AA evoked a vigorous inflammatory response in 129 and DBA mice, whereas only a modest response was seen in B6 animals. The response to AA in 129 and DBA strains is LT dependent. In contrast, LT make little contribution to this response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent, since this response was substantially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains. In contrast, the response to AA in the peritoneal cavity is robust in the 129 and B6 strains, but was significantly blunted in DBA mice, showing that strain differences in the response to AA are tissue specific. Variations in these and other experimental models of inflammation appear to correlate directly with the ability of a particular mouse strain and a specific tissue to respond to LT, specifically LTC4. Taken together, these findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also between different tissues within these inbred mouse lines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

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“…Moreover, LTB 4 is a potent chemotactic and chemokinetic agent that recruits proinflammatory cells towards sites of inflammation [40]. But also tumorigenesis, particularly of colon, breast, prostate, and lung carcinoma has been associated with excessive PGE 2 and LT formation [16,18,19].…”

Section: Page 21 Of 39mentioning

confidence: 99%

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Koeberle

Northoff

Werz

2009

Biochemical Pharmacology

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To cite this version:Andreas Koeberle, Hinnak Northoff, Oliver Werz. Identification of 5-lipoxygenase and microsomal prostaglandin E synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol. Biochemical Pharmacology, Elsevier, 2009, 77 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Ca 2+ -ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF 1α , or isolated human recombinant COX-2 were significantly affected by garcinol (≤ 30 µM). Together, the high potency of garcinol to selectively suppress PGE 2 synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.

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“…LTB 4 is a potent chemoattractant for leukocytes causing adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions, whereas cysLTs are potent bronchoconstrictors increasing vascular permeability and stimulating mucus secretion from airways [5]. These biological actions of LTs are mediated by specific G protein-coupled receptors (GPCRs) on the surface of their target cells.…”

Section: Biological Effects Of Leukotrienesmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

151

135

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

Abstract: Abstract. Claesson H-E, Dahlén S-E (Karolinska

Cited by 101 publications

References 241 publications

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

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